Di Huang1,2, Fan Zhang2, Haitao Tao2, Sujie Zhang2, Junxun Ma2, Jinliang Wang2, Zhefeng Liu2, Pengfei Cui2,3, Shixue Chen2,3, Ziwei Huang1,2, Zhaozhen Wu1,2, Lei Zhao2, Yi Hu4,5. 1. School of Medicine, Nankai University, 94 Weijin Road, Nankai, Tianjin, 300071, People's Republic of China. 2. Department of Medical Oncology, Chinese People's Liberation Army General Hospital, 28 Fuxing Road, Haidian, Beijing, 100853, People's Republic of China. 3. Department of Graduate Administration, Chinese PLA General Hospital, Beijing, People's Republic of China. 4. School of Medicine, Nankai University, 94 Weijin Road, Nankai, Tianjin, 300071, People's Republic of China. huyi_0912@126.com. 5. Department of Medical Oncology, Chinese People's Liberation Army General Hospital, 28 Fuxing Road, Haidian, Beijing, 100853, People's Republic of China. huyi_0912@126.com.
Abstract
BACKGROUND: Immunotherapy based on programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors has revolutionized the treatment of non-small cell lung cancer (NSCLC). Patients with high PD-L1 expression or DNA mismatch repair deficiency (dMMR)/microsatellite instability-high (MSI-H) cancer are reported to benefit from PD-1/PD-L1 inhibitors. However, additional biomarkers are needed, and whether tumor mutation burden (TMB) can be a robust biomarker or not is still controversial. OBJECTIVE: We conducted this study to assess TMB as a biomarker for PD-1/PD-L1 inhibitor treatment in advanced NSCLC patients in a real-world setting. PATIENTS AND METHODS: Chinese NSCLC patients who received a PD-1/PD-L1 inhibitor at the People's Liberation Army General Hospital and who had pathological tissues available for TMB were retrospectively analyzed. Demographic and clinical information were evaluated. Targeted next-generation sequencing (NGS) of the tumor tissue was performed. The relationship between TMB and clinical benefit was assessed. RESULTS: Thirty-four patients treated with PD-1/PD-L1 inhibitors between March 2015 and January 2019 were analyzed. The TMB was greater in patients with complete response (CR)/partial response (PR) versus stable disease (SD) versus progressive disease (PD) (median 11 vs. 9.7 vs. 4.2 mutations/megabase [Mb]; p = 0.049). The median progression-free survival was 10.6 months in the TMB-high group versus 3.9 months in the TMB-low group (cut-off value = 10 mutations/Mb) (hazard ratio [HR] 0.26 [95% confidence interval 0.12-0.57], p = 0.0007). The median overall survival was 21.0 months and 11.6 months (HR 0.37 [0.17-0.81], p = 0.0126) in the TMB-high group and the TMB-low group, respectively. The disease control rate was higher in the TMB-high group than in the TMB-low group (100% vs. 70%, p = 0.024). CONCLUSIONS: High TMB was associated with a better outcome in advanced NSCLC patients who received PD-1/PD-L1 inhibitors in China. Further studies are needed to confirm our findings.
BACKGROUND: Immunotherapy based on programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors has revolutionized the treatment of non-small cell lung cancer (NSCLC). Patients with high PD-L1 expression or DNA mismatch repair deficiency (dMMR)/microsatellite instability-high (MSI-H) cancer are reported to benefit from PD-1/PD-L1 inhibitors. However, additional biomarkers are needed, and whether tumor mutation burden (TMB) can be a robust biomarker or not is still controversial. OBJECTIVE: We conducted this study to assess TMB as a biomarker for PD-1/PD-L1 inhibitor treatment in advanced NSCLC patients in a real-world setting. PATIENTS AND METHODS: Chinese NSCLC patients who received a PD-1/PD-L1 inhibitor at the People's Liberation Army General Hospital and who had pathological tissues available for TMB were retrospectively analyzed. Demographic and clinical information were evaluated. Targeted next-generation sequencing (NGS) of the tumor tissue was performed. The relationship between TMB and clinical benefit was assessed. RESULTS: Thirty-four patients treated with PD-1/PD-L1 inhibitors between March 2015 and January 2019 were analyzed. The TMB was greater in patients with complete response (CR)/partial response (PR) versus stable disease (SD) versus progressive disease (PD) (median 11 vs. 9.7 vs. 4.2 mutations/megabase [Mb]; p = 0.049). The median progression-free survival was 10.6 months in the TMB-high group versus 3.9 months in the TMB-low group (cut-off value = 10 mutations/Mb) (hazard ratio [HR] 0.26 [95% confidence interval 0.12-0.57], p = 0.0007). The median overall survival was 21.0 months and 11.6 months (HR 0.37 [0.17-0.81], p = 0.0126) in the TMB-high group and the TMB-low group, respectively. The disease control rate was higher in the TMB-high group than in the TMB-low group (100% vs. 70%, p = 0.024). CONCLUSIONS: High TMB was associated with a better outcome in advanced NSCLC patients who received PD-1/PD-L1 inhibitors in China. Further studies are needed to confirm our findings.
Authors: David P Carbone; Martin Reck; Luis Paz-Ares; Benjamin Creelan; Leora Horn; Martin Steins; Enriqueta Felip; Michel M van den Heuvel; Tudor-Eliade Ciuleanu; Firas Badin; Neal Ready; T Jeroen N Hiltermann; Suresh Nair; Rosalyn Juergens; Solange Peters; Elisa Minenza; John M Wrangle; Delvys Rodriguez-Abreu; Hossein Borghaei; George R Blumenschein; Liza C Villaruz; Libor Havel; Jana Krejci; Jesus Corral Jaime; Han Chang; William J Geese; Prabhu Bhagavatheeswaran; Allen C Chen; Mark A Socinski Journal: N Engl J Med Date: 2017-06-22 Impact factor: 91.245
Authors: Edward B Garon; Naiyer A Rizvi; Rina Hui; Natasha Leighl; Ani S Balmanoukian; Joseph Paul Eder; Amita Patnaik; Charu Aggarwal; Matthew Gubens; Leora Horn; Enric Carcereny; Myung-Ju Ahn; Enriqueta Felip; Jong-Seok Lee; Matthew D Hellmann; Omid Hamid; Jonathan W Goldman; Jean-Charles Soria; Marisa Dolled-Filhart; Ruth Z Rutledge; Jin Zhang; Jared K Lunceford; Reshma Rangwala; Gregory M Lubiniecki; Charlotte Roach; Kenneth Emancipator; Leena Gandhi Journal: N Engl J Med Date: 2015-04-19 Impact factor: 91.245
Authors: Julie Brahmer; Karen L Reckamp; Paul Baas; Lucio Crinò; Wilfried E E Eberhardt; Elena Poddubskaya; Scott Antonia; Adam Pluzanski; Everett E Vokes; Esther Holgado; David Waterhouse; Neal Ready; Justin Gainor; Osvaldo Arén Frontera; Libor Havel; Martin Steins; Marina C Garassino; Joachim G Aerts; Manuel Domine; Luis Paz-Ares; Martin Reck; Christine Baudelet; Christopher T Harbison; Brian Lestini; David R Spigel Journal: N Engl J Med Date: 2015-05-31 Impact factor: 91.245
Authors: Martin Reck; Delvys Rodríguez-Abreu; Andrew G Robinson; Rina Hui; Tibor Csőszi; Andrea Fülöp; Maya Gottfried; Nir Peled; Ali Tafreshi; Sinead Cuffe; Mary O'Brien; Suman Rao; Katsuyuki Hotta; Melanie A Leiby; Gregory M Lubiniecki; Yue Shentu; Reshma Rangwala; Julie R Brahmer Journal: N Engl J Med Date: 2016-10-08 Impact factor: 91.245
Authors: Naiyer A Rizvi; Matthew D Hellmann; Alexandra Snyder; Pia Kvistborg; Vladimir Makarov; Jonathan J Havel; William Lee; Jianda Yuan; Phillip Wong; Teresa S Ho; Martin L Miller; Natasha Rekhtman; Andre L Moreira; Fawzia Ibrahim; Cameron Bruggeman; Billel Gasmi; Roberta Zappasodi; Yuka Maeda; Chris Sander; Edward B Garon; Taha Merghoub; Jedd D Wolchok; Ton N Schumacher; Timothy A Chan Journal: Science Date: 2015-03-12 Impact factor: 47.728
Authors: Hossein Borghaei; Luis Paz-Ares; Leora Horn; David R Spigel; Martin Steins; Neal E Ready; Laura Q Chow; Everett E Vokes; Enriqueta Felip; Esther Holgado; Fabrice Barlesi; Martin Kohlhäufl; Oscar Arrieta; Marco Angelo Burgio; Jérôme Fayette; Hervé Lena; Elena Poddubskaya; David E Gerber; Scott N Gettinger; Charles M Rudin; Naiyer Rizvi; Lucio Crinò; George R Blumenschein; Scott J Antonia; Cécile Dorange; Christopher T Harbison; Friedrich Graf Finckenstein; Julie R Brahmer Journal: N Engl J Med Date: 2015-09-27 Impact factor: 91.245
Authors: Arne Warth; Sandrina Körner; Roland Penzel; Thomas Muley; Hendrik Dienemann; Peter Schirmacher; Magnus von Knebel-Doeberitz; Wilko Weichert; Matthias Kloor Journal: Virchows Arch Date: 2015-12-04 Impact factor: 4.064
Authors: Hira Rizvi; Francisco Sanchez-Vega; Konnor La; Walid Chatila; Philip Jonsson; Darragh Halpenny; Andrew Plodkowski; Niamh Long; Jennifer L Sauter; Natasha Rekhtman; Travis Hollmann; Kurt A Schalper; Justin F Gainor; Ronglai Shen; Ai Ni; Kathryn C Arbour; Taha Merghoub; Jedd Wolchok; Alexandra Snyder; Jamie E Chaft; Mark G Kris; Charles M Rudin; Nicholas D Socci; Michael F Berger; Barry S Taylor; Ahmet Zehir; David B Solit; Maria E Arcila; Marc Ladanyi; Gregory J Riely; Nikolaus Schultz; Matthew D Hellmann Journal: J Clin Oncol Date: 2018-01-16 Impact factor: 44.544
Authors: Tony S K Mok; Yi-Long Wu; Iveta Kudaba; Dariusz M Kowalski; Byoung Chul Cho; Hande Z Turna; Gilberto Castro; Vichien Srimuninnimit; Konstantin K Laktionov; Igor Bondarenko; Kaoru Kubota; Gregory M Lubiniecki; Jin Zhang; Debra Kush; Gilberto Lopes Journal: Lancet Date: 2019-04-04 Impact factor: 79.321